Cytochrome oxidase function

However, today a wealth of evidence suggests that cytochrome oxidase functions as a redox-linked proton pump [155] (reviewed in Refs. 8, 14, 47, 52, 92, 99). Two electrical charge equivalents are proposed to cross the membrane per transferred electron two protons are taken up from the M side, one of which is transported to the C side (Fig. 3.6). This function has been confirmed also for cytochrome oxidase liposomes [52,54,55,156-161], and includes work with bacterial cytochrome oxidase... 

In spite of the absence of integral mitochondria, the red cell contains some of the enzymes (fumerase, isocitric dehydrogenase, malic dehydrogenase, and cytochrome oxidase) functioning in the Krebs cycle and electron transport. These enzymes probably represent mitochondrial remnants, and their presence in the mature erythrocyte may be a consequence of their greater stability. Similarly, enzymes concerned with... 

Boulatov R, Collman JP, Shiryaeva IM, Sunderland CJ. 2002. Functional analogs of the O2 reduction site of cytochrome oxidase Mechanistic aspects and possible effects of Cug. J Am Chem Soc 124 11923... 

Sands, R.H. and Beinert, H. 1959. On the function of copper in cytochrome oxidase. Biochemical and Biophysical Research Communications 1 175-178. 

Adults require 1-2 mg of copper per day, and eliminate excess copper in bile and feces. Most plasma copper is present in ceruloplasmin. In Wilson s disease, the diminished availability of ceruloplasmin interferes with the function of enzymes that rely on ceruloplasmin as a copper donor (e.g. cytochrome oxidase, tyrosinase and superoxide dismutase). In addition, loss of copper-binding capacity in the serum leads to copper deposition in liver, brain and other organs, resulting in tissue damage. The mechanisms of toxicity are not fully understood, but may involve the formation of hydroxyl radicals via the Fenton reaction, which, in turn initiates a cascade of cellular cytotoxic events, including mitochondrial dysfunction, lipid peroxidation, disruption of calcium ion homeostasis, and cell death. 

Proteins involved in the fundamental structure and function of neurons are decreased in schizophrenia. Several postmortem studies have identified consistent reductions in the expression of mitochondrial associated genes involved in oxidative metabolism, such as cytochrome oxidase and cytochrome C reductase [23], Reduced oxidative metabolism is consistent with evidence of increased brain lactate,... 

Over the years, there have been numerous reports of oxidase preparations that contain polypeptide components, additional to those described above. As yet no molecular probes are available for these, and so their true association with the oxidase is unconfirmed. There are many reports in the literature describing the role of ubiquinone as an electron transfer component of the oxidase, but its involvement is controversial. Quinones (ubiquinone-10) have reportedly been detected in some neutrophil membrane preparations, but other reports have shown that neither plasma membranes, specific granules nor most oxidase preparations contain appreciable amounts of quinone, although some is found in either tertiary granules or mitochondria. Still other reports suggest that ubiquinone, flavoprotein and cytochrome b are present in active oxidase preparations. Thus, the role of ubiquinone and other quinones in oxidase activity is in doubt, but the available evidence weighs against their involvement. Indeed, the refinement of the cell-free activation system described above obviates the requirement for any other redox carriers for oxidase function. 

It is known that protein kinase C can phosphorylate a number of key oxidase components, such as the two cytochrome b subunits and the 47-kDa cytoplasmic factor. This process is prevented by protein kinase C inhibitors such as staurosporine (although it is now recognised that this inhibitor is not specific for protein kinase C), which also inhibits the respiratory burst activated by agonists such as PMA. However, when cells are stimulated by fMet-Leu-Phe, translocation of pAl-phox to the plasma membrane can occur even if protein kinase C activity is blocked - that is, phosphorylation is not essential for the translocation of this component in response to stimulation by this agonist. Similarly, the kinetics of phosphorylation of the cytochrome subunits do not follow the kinetics of oxidase activation, and protein kinase C inhibitors have no effect on oxidase activity elicited by some agonists -for example, on the initiation of the respiratory burst elicited by agonists such as fMet-Leu-Phe (Fig. 6.14). Furthermore, the kinetics of DAG accumulation do not always follow those of oxidase activity. Hence, whilst protein kinase C is undoubtedly involved in oxidase activation by some agonists, oxidase function is not totally dependent upon the activity of this kinase. 

These observations were taken further by examining whether y-interferon treatment could up-regulate NADPH oxidase function in CGD neutrophils and monocytes. It was found that 12 out of 13 patients with autosomal recessive CGD had increased oxidase activity upon y-interferon exposure the only patient not responding was the one devoid of the b cytochrome. In X-linked CGD, 9 of 13 showed no improvement, whereas 3 showed some improvement and 1 had oxidase activity increased to near-normal levels. Patients with atypical X-linked CGD (i.e. low oxidase activity and some cytochrome b) appear to respond best to y-interferon treatment. Interferons-a and -ft are without affect. This enhancement of oxidase function (detected by NBT slide tests and O2 production) is due, at least in part, to increased levels of mRNA for the heavy chain of cytochrome b. In the absence of y-interferon treatment, monocyte-derived macrophages have extremely low or undetectable levels of mRNA for the cytochrome b heavy chain however, this is increased about fivefold (to about 5% of normal) after y-interferon treatment. 

The order in which the heme compounds reacted with oxygen was not firmly established nor was the distinction in function between cytochrome c, an electron carrier, and cytochrome oxidase, the enzyme catalyzing the oxidation of ferrocytochrome c by oxygen to give ferri-cytochrome c, (cyt c-Fe3+). 

Cyanide ion exerts an inhibitory action on certain metabolic enzyme systems, most notably cytochrome oxidase, the enzyme involved in the ultimate transfer of electrons to molecular oxygen. Because cytochrome oxidase is present in practically all cells that function under aerobic conditions, and because the cyanide ion diffuses easily to all parts of the body, cyanide quickly halts practically all cellular respiration. The venous blood of a patient dying of cyanide is bright red and resembles arterial blood because the tissues have not been able to utilize the oxygen brought to them. Cyanide intoxication produces lactic acidosis, the result of an increased rate of glycolysis and production of lactic acid. ... 

Nitrite reductases and nitrous oxide reductases are relatively newly found copper-containing proteins involved in bacterial denitrification. N2O reductase may bear a relationship to cytochrome oxidase and, indeed, parallels it somewhat in function, being the terminal electron acceptor in its pathway. 

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